Comparison of Capping Tendency of Directly Compressible Mannitol Powders

INTRODUCTION

Mannitol is the preferred excipient choice for APIs (active pharmaceutical ingredients) with stability problems in final drug formulations. Mannitol presents a high chemical stability and is considered as compatible with almost all drugs. Mannitol is the only excipient having two opposite properties: water solubility (18 g/100 ml at 20°C) and low hygroscopicity (pure mannitol powder does not adsorb water at 20°C up to 96% relative humidity).

Texturized mannitol powders have been developed specifically for direct compression,¹ enabling easy tableting. Among them, spray-dried mannitol powders have been successfully used for a long time. Nevertheless, when increasing the production speed, mannitol does not always result in hard tablets, as capping occurs at short dwell time, capping occurs. This capping occurs typically when increasing tableting speed and/or the compression force on convex tablets. It might be an obstacle upscaling successfully running industrial products. 
The aim of this study is to understand how the mannitol structure interferes with the observed capping phenomena. 

OBJECTIVES

Application trials with several commercially available mannitol grades help to compare their tableting performance. Main attention was paid to monitor the capping tendency in function of the tableting speed and of the compression force. For maximizing the capping risk, mannitol was tested in combination with a highly challenging API, sitagliptin powder. For the same reason, all tableting trials were done without any precompression.

MATERIALS AND METHODS

Materials

PEARLITOL® 200 GT mannitol from Roquette Frères (Lestrem, France) 

Two different DC mannitol grades from the market: 
Competitor A: spray-dried mannitol
Competitor B: low density granulated mannitol
Vegetal magnesium stearate (Roquette Magnesium Stearate)
Sitagliptin phosphate monohydrate powder (Starpharm China)

Methods

Blending

Mannitol and sitagliptin were mixed for 5 min in a Turbula mixer (WAB-Group, Muttenz, Switzerland). Additional mixing for 5 min was done after adding the magnesium stearate.

Powder characteristics

The bulk and tapped densities of the ready-made powder blends were measured on Stampfvolumeter STAV 2003 equipment (J. Engelsmann AG, Ludwigshafen, Germany).

Tableting

All tableting trials were done on rotary tablet press simulator STYLCAM 200R (MedelPharm), using the “came direct” profile.
Punches: Euro B Elizabeth D10R10
Die: Euro B Elizabeth D10
Tablet weight: 400 mg
Compression force: 5, 10, 15, 20 kN
Precompression force: 0 kN
Tableting speed: 10, 25 and 40 tablets per minute (equivalent to a rotary press speed of about 60,000 / 150,000 / 250,000 tablets/hour).

Tablet characterization

All tablets were visually inspected; capped tablets are recorded without any further characterization. Per test, 30 tablets were analyzed on their dimensions, weight and hardness, using a Pharmatron ST 50 (Solothurn, Switzerland) equipment.

RESULTS

Always the ready-made powder blends reveal differences. Not all these blends (especially not with competitor B) would be usable for direct compression due to missing powder flow (see table 1).

Table 1. Powder characteristics

The tableting trials show the differences of the real tableting capacity of these mannitol grades. Only the use of PEARLITOL® 200 GT permits the production of tablets, both with 20% and with 25% drug load (see figure 1). No capping was observed, independently of the used tableting speed. A clear correlation between tablet hardness and applied compression force exists, without any indication for capping. 

Figure 1. The tableting results with PEARLITOL® 200 GT

Figure 2 summarizes completely different findings for competitor A, a spray-dried mannitol. It is completely impossible to obtain tablets with 25% sitagliptin. At lower drug load, tableting was only feasible at lower compression forces.

Figure 2. The tableting results with the competitor product A

Low density granulated mannitol, competitor B, presents the same tendency to capping (see figure 3). Hardness data show that capping increases with compression force increase and with sitagliptin ratio increase. With 25% sitagliptin, the desired 100 N tablet hardness is not reached. 

Figure 3. The tableting results with the competitor product B

CONCLUSION

A rotary tablet press simulator was used to compare the behavior at high tableting speed and at increasing compression force of three different grades of directly compressible mannitol powders. These stressful conditions had a very limited impact on the performance of the new PEARLITOL® 200 GT, only a slight decrease of the tablet hardness. In comparison, capping was observed with the two different DC mannitol grades from the market (competitor A: spray-dried mannitol, competitor B: low density granulated mannitol) when increasing the tableting speed. Moreover, using both DC mannitol powders, it was not possible to obtain tablets with the 100 N desired tablet hardness when increasing the sitagliptin ratio.

REFERENCES

1. Tarlier, N, et al. Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator. Int. J. of Pharm. 495 (2015) 410-41

https://doi.org/10.1016/j.ijpharm.2015.09.007

2. Kosugi, A, et al, Effect of Different Direct Compaction Grades of Mannitol on the Storage Stability of Tablet Properties Investigated Using a Kohonen Self-Organizing Map and Elastic Net Regression Model, Pharmaceutics 2020, 12, 886.

https://doi.org/10.3390/pharmaceutics12090886